We recently discovered that human sinonasal solitary chemosensory cells (SCCs) express T2R bitter taste receptors that, when activated, stimulate Ca2+ -driven secretion of antimicrobial peptides (AMPs) from surrounding epithelial cells, playing an important role in innate immunity. We hypothesize that, in vivo, SCCs use T2Rs to respond to bitter bacterial products by activating AMP secretion. Furthermore, SCC T2R-mediated Ca2+ responses are inhibited the T1R3 sweet receptor in response to artificial sweeteners, sweet D-amino acids (produced by many bacteria), and physiologically-relevant glucose concentrations in the airway surface liquid (ASL). This inhibition may occur through T1R-activation of cAMP signaling. Immunofluroescence suggests that T2R and T1R3 receptors are expressed within the same SCCs, likely coupled to different intracellular signaling pathways. We hypothesize that T1R-mediated inhibition of T2Rs exists to partially inhibit AMP release during times of relative health, as complete secretion and depletion of AMPs may leave the epithelium excessively vulnerable. During acute infection, bacteria may consume available ASL glucose, decreasing glucose concentration and deactivating T1R inhibition of T2Rs, allowing AMP release. The ability of T1Rs to inhibit AMP secretion is also modulated by airway surface liquid (ASL) pH, which may represent a host adaptive mechanism to counter D-amino acid production by bacteria. While we have defined much of human SCC T2R signaling, this T1R pathway is unknown. Our central hypothesis is that T1R2 and/or T1R3 sweet receptor subunits and T2Rs, expressed in the same sinonasal SCCs, are coupled to different intracellular signaling pathways. To test this, we will take sinonasal tissue explants and differentiated primary cultures of human and mouse sinonasal cells and (1) use immunofluorescence to examine T1R distribution in human SCCs, (2) identify T1R signal transduction pathway(s) in SCCs, including deriving pure or enriched cultures of mouse SCCs to biochemically characterize SCC T1R signaling, and (3) examine the mechanism of ASL pH regulation of SCC T1R signaling. We will also genotype human Tas1R2 and Tas1R3 polymorphisms to determine their influence on T1R signaling in SCCs. The goal of these aims is to identify the localization and signal transduction of sinonasal T1R receptors, which may be very important to developing new therapies for respiratory infections. ASL glucose is abnormally elevated in certain conditions such as diabetes mellitus and chronic rhinosinusitis, both of which often involve chronic respiratory infections. Excessive ASL glucose may overly inhibit T2R-mediated innate immunity, making T1R antagonists (eg, lactisole) therapeutic options to restore innate immune responses in certain patients. Moreover, if Tas1R2/3 polymorphisms play an important role in sinonasal T1R function, then future studies could reveal that Tas1R genetics and/or taste testing may be useful for making predictions about susceptibility to upper respiratory infections and/or the effectiveness of T1R-targeted therapeutics.